F-box/LRR-repeat protein 12 reorchestrated microglia to inhibit scarring and achieve adult spinal cord injury repair

Abstract Scarring is an insurmountable obstacle for axonal regeneration in recovery from spinal cord injury (SCI). It impedes the repair effects of therapeutic targets in cortical neurons, such as PTEN−/− and hyper-IL-6, which cannot break through dense scar barriers to reconstruct neural circuits. However, methods for eliminating this process remain elusive. Here, we conducted a multiomics analysis of SCI and identified FBXL12 as an effective target for inhibiting scarring, further promoting spontaneous crossing of axons at the epicenter. We identified N6-Methyladenosine (m6A) modification as the predominant mRNA modification in SCI, with Fbxl12 being a major modification target. Furthermore, m6A modification specifically promoted FBXL12 synthesis in activated microglia. The overexpression of FBXL12 in microglia contributed to its homogeneous distribution and maintained a “scar-less healing” phenotype. Remarkably, FBXL12 therapy effectively reduced extracellular matrix deposition and decreased the scar area by ~70%. Importantly, axons grew through the epicenter and reached a length of more than 2.4 mm 56 days post-SCI, significantly improving motor function and reconstructing the neural circuit. Mechanistically, FBXL12 promoted cytoskeletal reorganization and migration in microglia by catalyzing the K63-linked ubiquitylation of Myosin heavy chain 14 (MYH14). Together, our results identify m6A-FBXL12-MYH14 axis as a novel cytoskeletal reorganization pathway in activated microglia and suggest FBXL12 as an effective target for a novel microglia-based approach to facilitate scarless functional recovery in SCI.